Structure-Activity Relationship Studies of Pyridine-Based Ligands and Identification of a Fluorinated Derivative for the Positron Emission Tomography Imaging of Cannabinoid Type 2 Receptors.

The cannabinoid type 2 receptor has emerged as valuable target for therapy and imaging of immune- mediated pathologies. With the aim to find a suitable radiofluorinated analogue of the previously reported CB2 PET radioligand [¹¹C]RSR-056, 38 fluorinated derivatives were synthesized and tested by in vitro binding assays. With a Ki (hCB2) of 6 nM and a selectivity factor of nearly 700 over CB1, target compound 3 exhibited optimal in vitro properties and was selected for evaluation as a PET radioligand. [¹⁸F]3 was obtained in an average radiochemical yield of 11±4% and molar activities between 33-114 GBq/µmol. Specific binding of [¹⁸F]3 to CB2 was demonstrated by in vitro autoradiography and in vivo PET experiments using CB2 ligand GW-405,833. Metabolite analysis revealed only intact [¹⁸F]3 in rat brain. [¹⁸F]3 detected CB2 upregulation in human ALS spinal cord tissue and may thus become a candidate for diagnostic use in humans.